The present invention relates to a novel pyrimidine derivative having an antitumor activity, a cytostatic activity, and an inhibitory activity against a signal derived from Ras oncogene products.
The oncogene xe2x80x9crasxe2x80x9d such as H-ras, K-ras, and N-ras is mutated and activated in many of neoplasms. The xe2x80x9cRasxe2x80x9d, the products of ras oncogene, strongly concerns tumorigenesis caused by acceleration of cell cycle and induction of expression of many of genes associated with a malignant conversion such as a vascular endothelial growth factor and type-IV collagenase. Especially, it is found that there is highly frequent ras mutation in solid tumor such as pancreatic cancer ( greater than 80%), colon cancer ( greater than 40%), and lung cancer ( greater than 20%) which are difficult to be cured by using existing chemotherapeutics. Therefore, it is considered that Ras is one of the most important target molecules in the development of the chemotherapeutics against them.
A farnesyl-protein-transferase (FPT) inhibitor (FPTI) is known as chemotherapeutics of which target are Ras (WO95/13059, WO95/25086, WO95/25092, WO95/34535, U.S. Pat. No. 5,608,067, and JP-A-7-112930).
In the cells expressing activated Ras, the excess signals reach cell nucleus through some signaling pathways and some signal transmitter molecules such as MAPK (Mitogen Activated Protein Kinase) and PI3K (Phosphatidylinositol-3-Kinase). The signals activate the transcription factors such as AP1 (Activator Protein-1) and ETS (E26 transformation specific) in the cell nucleus and then they induce the expression of many genes related to malignant features through transcription activation element such as Ras Responsive Element (RRE). Therefore, it is possible to repress the malignant conversion of the cancer cells, when the signal transmission (a signal derived from ras oncogene products) is inhibited. Inhibitors of a signal derived from Ras oncogene products, of which basic structure is similar to that of the compounds of the present invention, are described in WO00/04014.
In the above situation, the inventors of the present invention have studied on the antitumor agent having an inhibitory activity against a signal derived from Ras oncogene products.
The activation of gene expression through RRE is in proportion to a signal derived from Ras and the signal can be measured by the amount of its expression. The inventors of the present invention artificially made cells having activated Ras wherein expression of firefly luciferase gene, reporter gene, is regulated by RRE and carried out a screening of the inhibitors taking luciferase activity shown by the cells as an index of signals through Ras. As a result, the inventors of the present invention found that a series of pyrimidine derivatives have a strong inhibitory activity against a signal derived from Ras oncogene products.
The present invention relates to I) a compound represented by the formula (I): 
wherein R1, R2, R3, and R4 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, an optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or
R1 and R2, R3 and R4, and R2 and R3 each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered ring optionally containing O, N, or S, provided that R1 and R2, and R3 and R4 do not form a ring when R2 and R3 taken together form a ring;
R5 and R6 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro;
RB and RC are each independently hydrogen atom, alkyl, or alkyloxy; provided that in the case of both of RB and RC are hydrogen atom, R1 is hydrogen atom or alkyl, R2 is optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R3 and R4 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or R3 and R4 each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered ring optionally containing O, N, or S;
X is xe2x80x94N(R7)xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 wherein R7 is hydrogen atom or optionally substituted alkyl;
Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl;
Z is optionally substituted aryl or optionally substituted heteroaryl; its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
In more detail, the present invention relates to II)-XVI):
II) a compound described in I), represented by the formula (II): 
wherein R8, R9, R10, and R11 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, a non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;
RB and RC are each independently hydrogen atom, alkyl, or alkyloxy; provided that in the case of both of RB and RC are hydrogen atom, R8 is hydrogen atom or alkyl, R9 is substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R10 and R11 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;
W is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94N(RA)xe2x80x94 wherein RA is hydrogen atom or optionally substituted alkyl;
R5, R6, X, and Z are as defined above mentioned I); its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
III) a compound described in I), represented by the formula (III): 
wherein R5, R6, and Z are as defined above mentioned I); R8, R9, R10, R11, RB and RC are as defined above mentioned II);
its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
IV) a compound described in I), represented by the formula (IV): 
wherein R8, R9, R10 and R11 are as defined above mentioned II);
R12 is hydrogen atom or alkyl;
RD and RE are each independently hydrogen atom or alkyl; provided that in the case of both of RD and RE are hydrogen atom, R8 is hydrogen atom or alkyl, R9 is optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R10 and R11 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;
V is optionally substituted aryl; its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
V) a compound represented by the formula (V): 
wherein R5 and R6 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen atoms, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro;
RF and RG are each independently hydrogen atom, alkyl, or alkyloxy;
X is xe2x80x94N(R7)xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 wherein R7 is hydrogen atom or optionally substituted alkyl;
Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl;
Z is optionally substituted aryl or optionally substituted heteroaryl;
Q1 is xe2x80x94NR1R2, xe2x80x94OR1, or xe2x80x94SR1, T1 is xe2x80x94OR3 or xe2x80x94SR3 wherein R1, R2 and R3 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or
R1 and R3, and R2 and R3 each taken together with the adjacent heteroatom form 5- to 7-membered ring; its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
VI) a compound described in V), represented by the formula (VI): 
wherein Q2 is xe2x80x94NR8R9, xe2x80x94OR8, or xe2x80x94SR8, T2 is xe2x80x94OR10 or xe2x80x94SR10 wherein R8, R9 and R10 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;
W is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94N(RA)xe2x80x94 wherein RA is hydrogen atom or optionally substituted alkyl;
R5, R6, RF, RG, X, and Z are as defined above mentioned V); its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
In the case of R8 and R10 are bonded directly with O or S, R8 and R10 peferably are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, or acyl;
VII) a compound described in V), represented by the formula (VII): 
wherein R5, R6, RF, RG, and Z are as defined above mentioned V);
Q2 and T2 are as defined above mentioned VI) its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
VIII) a compound described in V), represented by the formula (VIII): 
wherein R12 is hydrogen or alkyl;
RH and RJ are each independently hydrogen atom or alkyl;
V is optically substituted aryl;
the other symbols are as defined above mentioned VI); its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
IX) a compound, its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate as described in any one of the above I) to V), wherein R1, R2, R3, and R4 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,
X) a compound, its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate as described in any one of the above VI) to VIII), wherein R8, R9, R10, and R11 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,
XI) a pharmaceutical composition which contains as active ingredient a compound as described in any one of I) to X),
XII) a pharmaceutical composition for use as an antitumor agent which contains as active ingredient a compound as described in any one of I) to X),
XIII) a pharmaceutical composition for use as a cytostatic agent which contains as described in any one of I) to X),
XIV) a pharmaceutical composition for use as an inhibitor against a signal derived from Ras oncogene products which contains as active ingredient a compound as described in any one of I) to X),
XV) use of a compound of any one of I) to X) for the preparation of a pharmaceutical composition for treating cancer, and
XVI) a method of treating a mammal, including a human, to alleviate a pathological effect of cancer, which comprises administration to the mammal of a compound as described in any one of I) to X).
The term xe2x80x9calkylxe2x80x9d employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 1 to 8 carbon atoms. Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. Preferably, C1 to C6 alkyl is exemplified. More preferably, C1 to C3 alkyl is exemplified.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more double bonds. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, prenyl, a variety of butenyl isomers and the like. Preferably, C2 to C6 alkenyl is exemplified. More preferably, C2 to C3 alkenyl is exemplified.
The term xe2x80x9calkynylxe2x80x9d employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more triple bonds. The alkynyl may contain (a) double bond(s). An example of the alkenyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, and the like. Preferably, C2 to C6 alkynyl is exemplified. More preferably, C2 to C3 alkynyl is exemplified.
The term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms in the present specification includes a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Preferably, phenyl, 1-naphthyl, and 2-naphthyl are exemplified. More preferably, phenyl is exemplified.
The term xe2x80x9caralkylxe2x80x9d in the present specification includes a group wherein the above-mentioned xe2x80x9calkylxe2x80x9d is substituted with the above-mentioned xe2x80x9carylxe2x80x9d. An example of aralkyl includes benzyl, phenethyl (e.g., 2-phenylethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl), anthrylmethyl (e.g., 9-anthrylmethyl) and the like. Preferably, benzyl and phenylethyl are exemplified.
The term xe2x80x9cheteroarylxe2x80x9d employed alone or in combination with other terms in the present specification includes a 5- to 6-membered aromatic cyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and may be fused with the above mentioned xe2x80x9carylxe2x80x9d, the later mentioned xe2x80x9ccarbocyclic groupxe2x80x9d, and xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d, or xe2x80x9cheteroarylxe2x80x9d. Heteroaryl is bonded at any possible position when the heteroaryl is a condensed ring. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 3-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4-imidazolyl), pyrazolyl (e.g., 3-pyrazolyl and 5-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 3-pyridyl and 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 4-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 2-furyl and 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl and 3-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), oxazolyl, thiadiazolyl (e.g., 1,3,4-thiadiazolyl and 1,2,4-thiadiazolyl), 4H-1,2,4-triazolyl, quinoxalinyl, 2-pyridon-3-yl, and the like. Preferably, pyridyl, pyrazinyl, furyl, thienyl and the like are exemplified.
The term xe2x80x9c5-membered heteroaryl-diylxe2x80x9d herein used includes a 5-membered divalent group derived from above-mentioned xe2x80x9cheteroarylxe2x80x9d. Examples of the 5-membered heteroaryl-diyl are furan-2,5-diyl, thiophene-2,5-diyl, pyrrole-2,5-diyl, pyrazole-3,5-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole3,5-diyl, oxazole-3,5-diyl, isoxazole-3,5-diyl, 1,3,4-thiadiazole-3,5-diyl, 1,2,4-thiadiazole-3,5-diyl, 4H-1,2,4-triazole-3,5-diyl, and the like.
The term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d employed alone or in combination with other terms in the present specification includes a 5- to 7-membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and a cyclic group wherein two or more of the above-mentioned heterocyclic groups arc fused. Examples of the heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl), piperidinyl (e.g., piperidino and 2-piperidinyl), piperazinyl (e.g., 1-piperazinyl), morpholinyl (e.g., morpholino and 3-morpholinyl), and the like.
The term xe2x80x9c5-membered non-aromatic heterocycle-diylxe2x80x9d herein used includes a 5-membered divalent group derived from the above-mentioned xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d. Examples of the 5-membered non-aromatic heterocycle-diyl are pyrrolidindiyl (e.g., pyrrolidine-2,5-diyl) and the like.
The term xe2x80x9ccarbocyclic groupxe2x80x9d herein used includes a 3- to 7-membered non-aromatic carbocyclic group. Examples of the carbocyclic group are cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl), cycloalkenyl (e.g., cyclopentenyl and cyclohexenyl), and the like.
In this specification, examples of the ring represented by xe2x80x9cR1 and R2, and R3 and R4 each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered non-aromatic heterocyclic ring optionally containing O, N, or Sxe2x80x9d are aziridine, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, pyrrole, pyrimidine, triazine, azepine, perhydroazepine, and the like.
In this specification, examples of the ring represented by xe2x80x9cR2 and R3 each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered non-aromatic heterocyclic ring optionally containing O, N, or Sxe2x80x9d are imidazolidine, hexahydropyridine, and perhydro-1,3-diazepine the like.
In this specification, examples of the ring represented by xe2x80x9cR1 and R3, or R2 and R3 each taken together with heteroatom form 5- to 7-membered non-aromatic heterocyclic ring optionally containing O, N, or Sxe2x80x9d are thiazolidine, perhydro-1,3-thiadine, oxazolidine, perhydro-1,3-oxadine, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane, 1,3-oxathiane, perhydro-1,3-oxazepine, perhydro-1,3-thiazepine, and the like.
The term xe2x80x9cacylxe2x80x9d employed alone or in combination with other terms in the present specification includes alkylcarbonyl of which alkyl part is the above-mentioned xe2x80x9calkylxe2x80x9d and arylcarbonyl of which aryl part is the above-mentioned xe2x80x9carylxe2x80x9d. Examples of the acyl are acetyl, propanoyl, benzoyl, and the like.
The term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo.
Examples of xe2x80x9calkyloxyxe2x80x9d herein used are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the like. Preferably, methyloxy, ethyloxy, n-propyloxy, and isopropyloxy are exemplified.
Examples of xe2x80x9calkylthioxe2x80x9d herein used are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like. Preferably, methylthio, ethylthio, n-propylthio, and isopropylthio are exemplified.
Examples of xe2x80x9calkyloxycarbonylxe2x80x9d herein used are methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, and the like.
The term xe2x80x9coptionally substituted aminoxe2x80x9d herein used means amino substituted with one or two of the above-mentioned xe2x80x9calkylxe2x80x9d, the above-mentioned xe2x80x9caralkylxe2x80x9d, the above-mentioned xe2x80x9cacylxe2x80x9d, optionally substituted arylsulfonyl (e.g., alkyloxyphenylsulfonyl), arylalkylene (e.g., benzylidene), alkylsulfonyl, carbamoyl and the like or non-substituted amino. Examples of the optionally substituted amino are amino, methylamino, ethylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, benzoylamino, acetylamino, propionylamino, tert-butyloxycarbonylamino, benzylidenamino, methylsulfonylamino, 4-methoxyphenylsulfonylamino, and the like. Preferably, amino, methylamino, dimethylamino, diethylamino, acetylamino are exemplified.
Substituents on the aromatic ring of xe2x80x9coptionally substituted aralkylxe2x80x9d are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), optionally substituted amino (e.g., amino, methylamino, dimethylamino, diethylamino, and benzylidenamino), alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and neopentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), formyl, lower alkanoyl (e.g., acetyl and propionyl), acyloxy (e.g., acetyloxy), acylamino, alkylsulfonyl (e.g., methylsulfonyl), and the like. These substituents may be substituted at one or more possible position(s).
Substituents of xe2x80x9coptionally substituted alkylxe2x80x9d, xe2x80x9coptionally substituted alkyloxyxe2x80x9d, and xe2x80x9coptionally substituted alkyloxycarbonylxe2x80x9d are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., amino, methylamino, dimethylamino, carbamoylamino, and tert-butyloxycarbonylamino), acyloxy (e.g., acetyloxy), optionally substituted aralkyloxy (e.g., benzyloxy and 4-methyloxybenzyloxy), and the like. These substituents may be substituted at one or more possible position(s).
Substituents of xe2x80x9coptionally substituted alkenylxe2x80x9d and xe2x80x9coptionally substituted alkynylxe2x80x9d are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., amino, methylamino, dimethylamino, carbamoylamino, and tert-butyloxycarbonylamino), acyloxy (e.g., acetyloxy), optionally substituted aralkyloxy (e.g., benzyloxy and 4-methyloxybenzyloxy), optionally substituted aryl (e.g., phenyl), and the like. These substituents may be substituted at one or more possible position(s).
The preferable examples of xe2x80x9coptionally substituted alkylxe2x80x9d are methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyclohexylmethyl, carboxyethyl, acetyloxyethyl, and benzyloxymethyl. More preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl are exemplified
Substituents of xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, xe2x80x9coptionally substituted 5-membered heteroaryl-diylxe2x80x9d, xe2x80x9coptionally substituted 5-membered non-aromatic heterocycle-diylxe2x80x9d, and xe2x80x9can optionally substituted non-aromatic heterocyclic groupxe2x80x9d are, for example, hydroxy, optionally substituted alkyloxy (e.g., methyloxy, ethyloxy, n-propyloxy, isopropyloxy, ethyloxycarbonylmethyloxy, carboxymethyloxy and 4-methoxybenzyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl, ethyloxycarbonyl, and tert-butyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), optionally substituted amino (e.g., amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylmethylamino, benzylidenamino, 4-methoxyphenylsulfonylamino, methylsulfonylamino, benzoylamino, acetylamino, propionylamino, and tert-butyloxycarbonylamino), optionally substituted sulfamoyl (e.g., sulfamoyl), optionally substituted alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, t-butyloxycarbonylaminomethyl, and aminomethyl), alkenyl (e.g., vinyl, propenyl, and prenyl), optionally substituted alkynyl (e.g., ethynyl and phenylethynyl), alkenyloxy (e.g., propenyloxy and prenyloxy), formyl, acyl (e.g., acetyl, propionyl, and benzoyl), acyloxy (e.g., acetyloxy), optionally substituted carbamoyl (e.g., carbamoyl and N,N-dimethylcarbamoyl), alkylsulfonyl (e.g., methylsulfonyl), aryl (e.g., phenyl), aralkyl (e.g., benzyl), carbothioamide, optionally substituted heterocyclic group (e.g., dioxolanyl, 2-methyl-1,3-dioxolan-2-yl, pyrrolidinyl, and piperidino), optionally substituted heteroaryl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridine N-oxide-4-yl, 1-methyl-2-pyridon-4-yl, 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), and the like. These substituents may be substituted at one or more possible position(s). Preferably, optionally substituted amino, halogen, nitro, alkyl, and alkyloxy are exemplified.
Examples of xe2x80x9coptionally substituted arylxe2x80x9d are phenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-acetylaminophenyl, 4-acetylaminophenyl, 2-benzoylaminophenyl, 4-benzoylaminophenyl, 2-methylsulfonylaminophenyl, 2-propionylaminophenyl, 2-methylaminophenyl, 4-methylaminophenyl, 2-dimethylaminophenyl, 4-dimethylaminophenyl, 2-ethylaminophenyl, 4-ethylaminophenyl, 4-diethylaminophenyl, 2-(4-methoxyphenylsulfonylamino)phenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 2-ethyloxycarbonylmethyloxyphenyl, 2-carboxymethyloxyphenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 4-methylphenyl, 4-methyloxyphenyl, 4-ethyloxyphenyl, 4-n-propyloxyphenyl, 4-isopropyloxyphenyl, 4-tert-butyloxycarbonylphenyl, 4-prenyloxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 4-(4-methoxybenzyloxy)phenyl, 4-methyloxycarbonylphenyl, 4-sulfamoylphenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-carboxyphenyl, 4-biphenylyl, 4-benzoylphenyl, 4-pyrrolidinophenyl, 4-piperidinophenyl, 3-aminonaphthalen-2-yl, 2-amino-5-chlorophenyl, 2-amino-3-chlorophenyl, 2-amino-4-chlorophenyl, 2-amino-6-chlorophenyl, 4-amino-2-chlorophenyl, 2-amino-4-fluorophenyl, 2-amino-5-fluorophenyl, 2-amino-6-fluorophenyl, 4-amino-2-fluorophenyl, 2-amino-4,5-difluorophenyl, 2-amino-3-methylphenyl, 2-amino-4-methylphenyl, 2-amino-5-methylphenyl, 2-amino-6-methylphenyl, 4-amino-3-methylphenyl, 4-amino-3-methyloxyphenyl, 2-amino-4-nitrophenyl, 4-amino-3-hydroxyphenyl, 2-amino-4-carboxyphenyl, 2-amino-4-methyloxycarbonylphenyl, 4-amino-2-hydroxyphenyl, 4-amino-3-(4-methoxypbenzyloxy)phenyl, 2,4-diaminophenyl, 3,4-diaminophenyl, 2-acetylmethylaminophenyl, 2-acetylamino-4-fluorophenyl, 2-acetylamino-4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-amino-2-methylphenyl, 2-fluoro-4-nitrophenyl, 4-amino-2-methyloxyphenyl, 2-methyloxy-4-nitrophenyl, 4-fluoro-2-nitrophenyl, 4-amino-2-trifluoromethylphenyl, 4-amino-2-ethyloxyphenyl, 4-amino-2-trifluoromethyloxyphenyl, 2-chloro-4-nitrophcnyl, 2-methyl-4-nitrophenyl, 4-nitro-2-trifluoromethyloxyphenyl, 4-nitro-2-trifluoromethylphenyl, 2-ethyloxy-4-nitrophenyl, and the like.
Examples of xe2x80x9coptionally substituted heteroarylxe2x80x9d are pyridin-3-yl, 2-aminopyridin-3-yl, 2-aminopyridin-5-yl, 3-aminopyrazin-2-yl, 3-aminopyrazol4-yl, 4-amino-2-methylpyrimidin-5-yl, 2-aminothiophen-3-yl, 3-methyl thiophen-2-yl, 5-methylthiophen-2-nyl, furan-2-yl, furan-3-yl, 2-methylfuran-3-yl, 2,5-dimethylfuran-3-yl, 5-bromofuran-2-yl, 2-nitrofuran4-yl, 1-methyl-4-nitropyrazol-3-yl, 1-methyl-4-nitropyrazol-5-yl, 5-nitropyrazol-3-yl, 4-nitropyrazol-3-yl, 2-(3-pyridyl)thiazol-4-yl, 2-(4-pyridyl)thiazol-4-yl, 6-(1-pyrrolyl)pyridin-3-yl, N-methyl-2-pyridon-3-yl, and the like.
Examples of xe2x80x9coptionally substituted 5-membered heteroaryl-diylxe2x80x9d are furan-2,5-diyl, thiophene-2,5-diyl, pyrrole-2,5-diyl, pyrazole-3,5-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, oxazole-2,5-diyl, isooxazole-3,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,2,4-thiadiazole-3,5-diyl, 4H-1,2,4-triazole-3,5-diyl, 1-methylpyrazole-3,5-diyl, and the like.
Preferable examples of R1 to R6, RB, RC, X, Y, and Z of the compound represented by the formula (I) are shown below as groups (a) to (t).
R1 and R2 are (a) one is hydrogen atom, the other is optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro.
R3 and R4 are (b) each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; (c) each independently hydrogen atom, alkyl optionally substituted with halogen atom, alkenyl, or alkynyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; and (d) one is hydrogen atom and the other is alkyl optionally substituted with halogen, alkenyl, or alkynyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro.
R5 is (e) hydrogen atom, alkyloxy, alkylthio, or optionally substituted alkyl; (f) hydrogen atom or alkyl; and (g) hydrogen atom or C1 to C2 alkyl.
R6 is (h) hydrogen atom or alkyl; and (i) hydrogen atom.
X is (j) xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; and (k) xe2x80x94Sxe2x80x94.
Y is (1) 5-membered heteroaryl-diyl; (m) 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 1,3,4-thiadiazole-2,5-diyl, or 1,2,4-thiadiazole-3,5-diyl; and (n) 1,3,4-oxadiazole-2,5-diyl.
Z is (o) optionally substituted aryl or optionally substituted heteroaryl; (p) optionally substituted phenyl or optionally substituted monocyclic heteroaryl; and (q) phenyl, pyridyl, thienyl, or furyl, which are substituted with 1 to 3 substituents selected from the group consisting of optionally substituted amino, halogen, alkyl, alkyloxy, acyl, phenyl, alkyloxycarbonyl, hydroxy, nitro, or haloalkyl.
A preferable example of RB and RC is (r) (RB, RC) is (alkyl, hydrogen atom) or (hydrogen atom, hydrogen atom); and (s) RB, RC) is (hydrogen atom, hydrogen atom).
A preferred group of compounds represented by the formula (I) is shown below. [(R1, R2), (R3, R4), R5, R6, X, Y, (RB, RC)]=[a, b, e, h, j, l, r], [a, b, e, h, j, l, s], [a, b, e, h, j, m, r], [a, b, e, h, j, m, s], [a, b, e, h, j, n, r], [a, b, e, h, j, n, s], [a, b, e, h, k, l, r], [a, b, e, h, k, l, s], [a, b, e, h, k, m, r], [a, b, e, h, k, m, s], [a, b, e, h, k, n, r], [a, b, e, h, k, n, s], [a, b, e, i, j, l, r], [a, b, e, i, j, l, s], [a, b, e, i, j, m, r], [a, b, e, i, j, m, s], [a, b, e, i, j, n, r], [a, b, s, i, j, n, s], [a, b, e, i, k, l, r], [a, b, e, i, k, l, s], [a, b, e, i, k, m, r], [a, b, e, i, k, m, s], [a, b, j, k, n, r], [a, b, e, i, k, n, s], [a, b, f, h, j, l, r], [a, b, f, h, j, l, s], [a, b, f, h, j, m, r], [a, b, f, h, j, m, s], [a, b, f, h, j, n, r], [a, b, f, h, j, n, s], [a, b, f, h, k, l, r], [a, b, f, h, k, l, s], [a, b, f, h, k, m, r], [a, b, f, h, k, m, s], [a, b, f, h, k, n, r], [a, b, f, h, k, n, s], [a, b, f, i, j, l, r], [a, b, f, i, j, l, s], [a, b, f, i, j, m, r], [a, b, f, i, j, m, s], [a, b, f, i, j, n, r], [a, b, f, i, j, n, s], [a, b, f, i, k, l, r], [a, b, f, i, k, l, s], [a, b, f, i, k, m, r], [a, b, f, i, k, m, s], [a, b, f, i, k, n, r], [a, b, f, i, k, n, s], [a, b, g, h, j, l, r], [a, b, g, h, j, l, s], [a, b, g, h, j, m, r], [a, b, g, h, j, m, s], [a, b, g, h, j, n, r], [a, b, g, h, j, n, s], [a, b, g, h, k, l, r], [a, b, g, h, k, l, s], [a, b, g, h, k, m, r], [a, b, g, h, k, m, s], [a, b, g, h, k, n, r], [a, b, g, h, k, n, s], [a, b, g, i, j, l, r], [a, b, g, i, j, l, s], [a, b, g, i, j, m, r], [a, b, g, i, j, m, s], [a, b, g, i, j, n, r], [a, b, g, i, j, n, s], [a, b, g, i, k, l, r], [a, b, g, i, k, l, s], [a, b, g, i, k, m, r], [a, b, g, i, k, m, s], [a, b, g, i, k, n, r], [a, b, g, i, k, n, s], [a, c, e, h, j, l, r], [a, c, e, b, j, l, s], [a, c, e, h, j, m, r], [a, c, e, h, j, m, s], [a, c, e, h, j, n, r], [a, c, e, h, j, n, s], [a, c, e, h, k, l, r], [a, c, e, h, k, l, s], [a, c, e, h, k, m, r], [a, c, e, h, k, m, s], [a, c, e, h, k, n, r], [a, c, e, h, k, n, s], [a, c, e, i, j, l, r], [a, c, e, i, j, l, s], [a, c, e, i, j, m, r], [a, c, e, i, j, m, s], [a, c, e, i, j, n, r], [a, c, e, i, j, n, s], [a, c, e, i, k, l, r], [a, c, e, i, k, l, s], [a, c, e, i, k, m, r], [a, c, e, i, k, m, s], [a, c, e, i, k, n, r], [a, c, e, i, k, n, s], [a, c, f, h, j, l, r], [a, c, f, h, j, l, s], [a, c, f, h, j, m, r], [a, c, f, h, j, m, s], [a, c, f, h, j, n, r], [a, c, f, h, j, n, s], [a, c, f, h, k, l, r], [a, c, f, h, k, l, s], [a, c, f, h, k, m, r], [a, c, f, h, k, m, s], [a, c, f, h, k, n, r], [a, c, f, h, k, n, s], [a, c, f, i, j, l, r], [a, c, f, i, j, l, s], [a, c, f, i, j, m, r], [a, c, f, i, j, m, s], [a, c, f, i, j, n, r], [a, c, f, i, j, n, s], [a, c, f, i, k, l, r], [a, c, f, i, k, l, s], [a, c, f, i, k, m, r], [a, c, f, i, k, m, s], [a, c, f, i, k, n, r], [a, c, f, i, k, n, s], [a, c, g, h, j, l, r], [a, c, g, h, j, l, s], [a, c, g, h, j, m, r], [a, e, g, h, j, m, s], [a, c, g, h, j, n, r], [a, c, g, h, j, n, s], [a, c, g, h, k, l, r], [a, c, g, h, k, l, s], [a, c, g, h, k, m, r], [a, c, g, h, k, m, s], [a, c, g, h, k, n, r], [a, c, g, h, k, n, s], [a, c, g, i, j, l, r], [a, c, g, i, j, l, s], [a, c, g, i, j, m, r], [a, c, g, i, j, m, s], [a, c, g, i, j, n, r], [a, c, g, i, j, n, s], [a, c, g, i, k, l, r], [a, c, g, i, k, l, s], [a, c, g, i, k, m, r], [a, c, g, i, k, m, s], [a, c, g, i, k, n, r], [a, c, g, i, k, n, s], [a, d, e, h, j, l, r], [a, d, e, h, j, l, s], [a, d, e, h, j, m, r], [a, d, e, h, j, m, s], [a, d, e, h, j, n, r], [a, d, e, h, j, n, s], [a, d, e, h, k, l, r], [a, d, e, h, k, l, s], [a, d, e, h, k, m, r], [a, d, e, h, k, m, s], [a, d, e, h, k, n, r], [a, d, e, h, k, n, s], [a, d, e, i, j, l, r], [a, d, e, i, j, l, s], [a, d, e, i, j, m, r], [a, d, e, i, j, m, s], [a, d, e, i, j, n, r], [a, d, e, i, j, n, s], [a, d, e, i, k, l, r], [a, d, e, i, k, l, s], [a, d, e, i, k, m, r], [a, d, e, i, k, m, s], [a, d, e, i, k, n, r], [a, d, e, i, k, n, s], [a, d, f, h, j, l, r], [a, d, f, h, j, l, s], [a, d, f, h, j, m, r], [a, d, f, h, j, m, s], [a, d, f, h, j, n, r], [a, d, f, h, j, n, s], [a, d, f, h, k, l, r], [a, d, f, h, k, l, s], [a, d, f, h, k, m, r], [a, d, f, h, k, m, s], [a, d, f, h, k, n, r], [a, d, f, h, k, n, s], [a, d, f, i, j, l, r], [a, d, f, i, j, l, s], [a, d, f, i, j, m, r], [a, d, f, i, j, m, s], [a, d, f, i, j, n, r], [a, d, f, i, j, n, s], [a, d, f, i, k, l, r], [a, d, f, i, k, l, s], [a, d, f, i, k, m, r], [a, d, f, i, k, m, s], [a, d, f, i, k, n, r], [a, d, f, i, k, n, s], [a, d, g, h, j, l, r], [a, d, g, h, j, l, s], [a, d, g, h, j, m, r], [a, d, g, h, j, m, s], [a, d, g, h, j, n, r], [a, d, g, h, j, n, s], [a, d, g, h, k, l, r], [a, d, g, h, k, l, s], [a, d, g, h, k, m, r], [a, d, g, h, k, m, s], [a, d, g, h, k, n, r], [a, d, g, h, k, n, s], [a, d, g, i, j, l, r], [a, d, g, i, j, l, s], [a, d, g, i, j, m, r], [a, d, g, i, j, m, s], [a, d, g, i, j, n, r], [a, d, g, i, j, n, s], [a, d, g, i, k, l, r], [a, d, g, i, k, l, s], [a, d, g, i, k, m, r], [a, d, g, i, k, m, s], [a, d, g, i, k, n, r], [a, d, g, i, k, n, s]
Preferred embodiments of this invention are compounds wherein Z is any one of (o) to (q) and [(R1, R2), (R3, R4), R5, R6, X, Y, (RB, RC)] is any one of the above combinations.
Preferable examples of R5, R6, RF, RG, Q1, T1, X, Y, and Z of the compound represented by the formula (V) arc shown below as groups (a) to (r).
R5 is (a) hydrogen atom, alkyloxy, alkylthio, or optionally substituted alkyl; (b) hydrogen atom or alkyl; and (c) hydrogen atom or C1 to C2 alkyl.
R3 is (d) hydrogen atom or alkyl; and (e) hydrogen atom.
A preferable example of RF and RG is (f) (RB, RC) is (hydrogen atom, hydrogen atom), (hydrogen atom, alkyl), (alkyl, alkyl), or (hydrogen atom, alkyloxy); and (g) is (hydrogen atom, hydrogen atom), (hydrogen atom, alkyl), or (alkyl, alkyl).
Q1 and T1 are (h) Q1 is xe2x80x94NR1R2 or xe2x80x94SR1 wherein R1 and R2 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, or alkynyl, T1 is xe2x80x94SR3 wherein R3 is hydrogen atom, optionally substituted alkyl, alkenyl, or alkynyl; (i) Q1 is xe2x80x94NR1R2 or xe2x80x94SR1 wherein R1 and R2 are each independently hydrogen atom, alkyl optionally substituted with halogen, alkenyl, or alkynyl, T1 is xe2x80x94SR3 wherein R3 is hydrogen atom, alkyl optionally substituted with halogen, alkenyl, or alkynyl; (j) Q1 is xe2x80x94NR1R2 or xe2x80x94SR1 wherein R1 and R2 are one is hydrogen atom and the other is C1 to C3 alkyl optionally substituted with halogen, T1 is xe2x80x94SR3 wherein R3 is hydrogen atom or alkyl optionally substituted with halogen.
X is (k) xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; and (l) xe2x80x94Sxe2x80x94.
Y is (m) 5-membered heteroaryl-diyl; (n) 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 1,3,4-thiadiazole-2,5-diyl, or 1,2,4-thiadiazole-3,5-diyl; and (o) 1,3,4-oxadiazole-2,5-diyl.
Z is (p) optionally substituted aryl or optionally substituted heteroaryl; (q) optionally substituted phenyl or optionally substituted monocyclic heteroaryl; and (r) phenyl, pyridyl, thienyl, or furyl, which are substituted with 1 to 3 substituents selected from the group consisting of optionally substituted amino, halogen, alkyl, alkyloxy, acyl, phenyl, alkyloxycarbonyl, hydroxy, nitro, or haloalkyl.
A preferred group of compounds represented by the formula (V) is shown below. [R5, R6, (RF, RG), (Q1, T1), X, Y]=[a, d, f, h, k, m], [a, d, f, h, k, n], [a, d, f, h, k, o], [a, d, f, h, l, m], [a, d, f, h, l, n], [a, d, f, h, l, o], [a, d, f, i, k, m], [a, d, f, i, k, n], [a, d, f, i, k, o], [a, d, f, i, l, m], [a, d, f, i, l, n], [a, d, f, i, l, o], [a, d, f, j, k, m], [a, d, f, j, k, n], [a, d, f, j, k, o], [a, d, f, j, l, m], [a, d, f, j, l, n], [a, d, f, j, l, o], [a, d, g, h, k, m], [a, d, g, h, k, n], [a, d, g, h, k, o], [a, d, g, h, l, m], [a, d, g, h, l, n], [a, d, g, h, l, o], [a, d, g, i, k, m], [a, d, g, i, k, n], [a, d, g, i, k, o], [a, d, g, i, l, m], [a, d, g, i, l, n], [a, d, g, i, l, o], [a, d, g, j, k, m], [a, d, g, j, k, n], [a, d, g, j, k, o], [a, d, g, j, l, m], [a, d, g, j, l, n], [a, d, g, j, l, o], [a, e, f, h, k, m], [a, e, f, h, k, n], [a, e, f, h, k, o], [a, e, f, h, l, m], [a, e, f, h, l, n], [a, e, f, h, l, o], [a, e, f, i, k, m], [a, e, f, i, k, n], [a, e, f, i, k, o], [a, e, f, i, l, m], [a, e, f, i, l, n], [a, e, f, i, l, o], [a, e, f, j, k, m], [a, e, f, j, k, n], [a, e, f, j, k, o], [a, e, f, j, l, m], [a, e, f, j, l, n], [a, e, f, j, l, o], [a, e, g, h, k, m], [a, e, g, h, k, n], [a, e, g, h, k, o], [a, e, g, h, l, m], [a, e, g h, l, n], [a, e, g, h, l, o], [a, e, g, i, k, m], [a, e, g, i, k, n], [a, e, g, i, k, o], [a, e, g, i, l, m], [a, e, g, i, l, n], [a, e, g, i, l, o], [a, e, g, j, k, m], [a, e, g, j, k, n], [a, e, g, j, k, o], [a, e, g, j, l, m], [a, e, g, j, l, n], [a, e, g, j, l, o], [b, d, f, h, k, m], [b, d, f, h, k, n], [b, d, f, h, k, o], [b, d, f, h, l, m], [b, d, f, h, l, n], [b, d, f, h, l, o], [b, d, f, i, k, m], [b, d, f, i, k, n], [b, d, f, i, k, o], [b, d, f, i, l, m], [b, d, f, i, l, n], [b, d, f, i, l, o], [b, d, f, j, k, m], [b, d, f, j, k, n], [b, d, f, j, k, o], [b, d, f, j, l, m], [b, d, f j, l, n], [b, d, f, j, l, o], [b, d, g, h, k, m], [b, d, g, h, k, n], [b, d, g, h, k, o], [b, d, g, h, l, m], [b, d, g, h, l, n], [b, d, g, h, l, o], [b, d, g, i, k, m], [b, d, g, i, k, n], [b, d, g, i, k, o], [b, d, g, i, l, m], [b, d, g, i, l, n], [b, d, g, i, l, o], [b, d, g, j, k, m], [b, d, g, j, k, n], [b, d, g, j, k, o], [b, d, g, j, l, m], [b, d, g, j, l, n], [b, d, g, j, l, o], [b, e, f, h, k, m], [b, e, f, h, k, n], [b, e, f, h, k, o], [b, e, f, h, l, m], [b, e, f, h, l, n], [b, e, f, h, l, o], [b, e, f, i, k, m], [b, e, f, i, k, n], [b, e f, i, k, o], [b, e, f, i, l, m], [b, e, f, i, l, n], [b, e, f, i, l, o], [b, e, f, j, k, m], [b, e, f, j, k, n], [b, e, f, j, k, o], [b, e, f, j, l, m], [b, e, f, j, l, n], [b, e, f, j, l, o], [b, e, g, h, k, m], [b, e, g, h, k, n], [b, e, g, h, k, o], [b, e, g, h, l, m], [b, e, g, h, l, n], [b, e, g, h, l, o], [b, e, g, i, k, m], [b, e, g, i, k, n], [b, e, g, i, k, o], [b, e, g, i, l, m], [b, e, g, i, l, n], [b, e, g, i, l, o], [b, e, g, j, k, m], [b, e, g, j, k, n], [b, e, g, j, k, o], [b, e, g, j, l, m], [b, e, j, l, n], [b, g, j, l, o], [c, d, f, h, k, m], [c, d, f, h, k, n], [c, d, f, h, k, o], [c, d, f, h, l, m], [c, d, f, h, l, n], [c, d, f, h, l, o], [c, d, f, i, k, m], [c, d, f, i, k, n], [c, d, f, i, k, o], [c, d, f, i, l, m], [c, d, f, i, l, n], [c, d, f, i, l, o], [c, d, f, j, k, m], [c, d, f, j, k, n], [c, d, f, j, k, o], [c, d, f, j, l, m], [c, d, f, j, l, n], [c, d, f, j, l, o], [c, d, g, h, k, m], [c, d, g, h, k, n], [c, d, g, h, k, o], [c, d, g, h, l, m], [c, d, g, h, l, n], [c, d, g, h, l, o], [c, d, g, i, k, m], [c, d, g, i, k, n], [c, d, g, i, k, o], [c, d, g, i, l, m], [c, d, g, i, l, n], [c, d, g, i, l, o], [c, d, g, j k, m], [c, d, g, j, k, n], [c, d, g, j, k, o], [c, d, g, j, l, m], [c, d, g, j, l, n], [c, d, g, j, l, o], [c, e, f, h, k, m], [c, e, f, h, k, n], [c, e, f, h, k, o], [c, e, f, h, l, m], [c, e, f, h, l, n], [c, e, f, h, l, o], [c, e, f, i, k, m], [c, e, f, i, k, n], [c, e, f, i, k, o], [c, e, f, i, l, m], [c, e f, i, l, n], [c, e, f, i, l, o], [c, e, f, j, k, m], [c, e, f, j, k, n], [c, e, f, j, k, o], [c, e, f, j, l, m], [c, e, j, l, n], [c, e, f, j, l, o], [c, e, g, h, k, m], [c, e, g, h, k, n], [c, e, g, h, k, o], [c, e, g, h, l, m], [c, e, g, h, l, n], [c, c, g, h, l, o], [c, e, g, i, k, m], [c, e, g i, k, n], [c, e, g, i, k, o], [c, e, g, i, l, m], [c, e, g, i, l, n], [c, e, g, i, l, o], [c, e, g, j, k, m], [c, e, g, j, k, n], [c, e, g, j, k, o], [c, e, g, j, l, m], [c, e, g, j, l, n], [c, e, g, j, l, o]
Preferred embodiments of this invention are compounds wherein Z is any one of (p) to (r) and [R5, R6, (RF, RG), (Q1, T1), X, Y] is any one of the above combinations.
In this specification, the compounds represented by the formula (I) may be represented by the below formula. 
The compounds represented by the formula (II), (III), and (IV) are as well as the above.
In this specification, a compound of formula (I) wherein R1 is hydrogen atom may be represented as an isomer of the formula (IX). 
wherein R2, R3, R4, R5, R6, RB, RC, X, Y, and Z are as defined above; R1 is hydrogen atom.
The compounds represented by the formula (II), (III), and (IV) are as well as the above.
In this specification, a compound of formula (V) wherein T1 is xe2x80x94SR3 wherein R3 is hydrogen atom may be represented as an isomer of the formula (X). The compounds wherein T1 is xe2x80x94OR3 wherein R3 is hydrogen atom are as well as the above. 
wherein R5, R6, RF, RG, Q1, X, Y, and Z are as defined above; R3 is hydrogen atom.
The compounds represented by the formulae (VI), (VII), and (VIII) are as well as the above.
In this specification, according to alkylation conditions for synthesis of the compounds (V) wherein T1 is xe2x80x94SR3 wherein R3 is alkyl, the compounds represented by the formula (X) may be obtained. The compounds wherein T1 is xe2x80x94OR3 wherein R3 is alkyl are as well as the above. 
wherein R5, R6, RF, RG, Q1, X, Y, and Z are as defined above; R3 is alkyl.
The compounds represented by the formulae (VI), (VII), and (VIII) arc as well as the above.
In this specification, the compounds of formula (I) wherein RB and RC are different, are represented as an optical active compound by the formulae (Ixe2x80x2) and (Ixe2x80x3). 
wherein R1, R2, R3, R4, R5, R6, RB, RC, X, Y, and Z are as defined above.
The compounds represented by the formulae (II), (III), (IV), (V), (VI), (VII), and (VIII) are as well as the above.
The compounds of the present invention represented by the formulae (I), (V), or (XIII) can be synthesized by the well-known methods described in a literature of chemistry. A summary of the useful methods for synthesis of the compounds of the present invention is shown below.
(Synthetic Method) 
wherein R5, R6, RB, RC, X, Y, and Z are as defined above; R13 is a protective group of a hydroxy group such as methyl, ethyl, trimethylsilyl, and tert-butyldimethylsilyl or hydrogen atom; Q3 is xe2x80x94NR1R2, xe2x80x94OR1, or xe2x80x94SR1; T3 is xe2x80x94NR3R4, xe2x80x94OR1, or xe2x80x94SR1 wherein R1, R2, R3, and R4 are as defined above.
The compound represented by the formula (XIII) can be synthesized by reacting Zxe2x80x94Yxe2x80x94XH (XI) with the pyrimidine derivatives (XII) mentioned later such as (XII-1) to (XII-4). The pyrimidine derivatives (XII) in a solvent such as water, acetic acid, and pyridine are treated with a hydrohalogenic acid such as hydrochloric acid and hydrobromic acid to give hydrogen halide salts of 5-halogenomethylpyrimidine. When R13 is hydrogen atom, a halogenation agent such as thionyl halide and phosphorous halide can be used. The obtained salts and Zxe2x80x94Yxe2x80x94XH (XI) in a solvent such as water, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, and tetrahydrofuran are reacted with an appropriate base, for example an inorganic base such as sodium hydroxide, potassium butoxide, sodium hydride, potassium hydride, and potassium carbonate or an organic base such as triethylamine, pyridine, and diisopropylethylamine at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 1 min to 24 h, preferably 10 min to 12 h to give the aimed compound (XIII).
Compound (XI) and compound (XII) can be synthesized by the methods A to I and the methods J to N as shown below.
In the methods A to I, Z represents optionally substituted aryl or optionally substituted heteroaryl. The starting material of each method is commercially available or can be synthesized by well-know method from the compound which is commercially available.
Method A: Synthetic method of the compound wherein Y is an oxadiazole ring and X is xe2x80x94Sxe2x80x94. 
wherein Z is above defined.
Compound (XIV) in a solvent such as ethanol and benzene is reacted with carbon disulfide and a base such as triethylamine, sodium hydroxide, and potassium carbonate at 0xc2x0 C. to 100xc2x0 C., preferably 60xc2x0 C. to 100xc2x0 C. for 10 min to 24 h, preferably 2 h to 12 h to give compound (XV-1).
Method B: Synthetic method of the compound wherein Y is an oxadiazole ring and X is xe2x80x94Oxe2x80x94. 
wherein Z is above defined.
To a solution of compound (XIV) in a solvent such as tetrahydrofuran and toluene, is added carbonyldiimidazole, and the mixture is reacted at 0xc2x0 C. to 120xc2x0 C., preferably 60xc2x0 C. to 120xc2x0 C. for 10 min to 24 h, preferably 2 h to 12 h to give compound (XV-2).
Method C: Synthetic method of the compound wherein Y is an oxadiazole ring and X is xe2x80x94N(R7)xe2x80x94. 
wherein Z is as defined above and R7 is as defined above.
To a solution of compound (XVI) in a solvent such as ethanol and tetrahydrofuran, is added mercury oxide, and the mixture is reacted at 0xc2x0 C. to 120xc2x0 C., preferably 30xc2x0 C. to 80xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 24 h to give compound (XV-3).
Method D: Synthetic method of the compound wherein Y is a thiadiazole ring and X is xe2x80x94Sxe2x80x94. 
wherein Z is as defined above.
To a solution of compound (XIV) in a solvent such as ethanol and tetrahydrofuran are added carbon disulfide and a base such as triethylamine and sodium hydroxide and the mixture is reacted at 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 60xc2x0 C. for 0.5 h to 24 h, 1 h to 12 h. After the solvent is removed, the residue is reacted with conc. sulfuric acid at xe2x88x9220xc2x0 C. to 40xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 1 min to 12 h, preferably 10 min to 1 h to give compound (XV-4).
Method E: Synthetic method of the compound wherein Y is a furan ring and X is xe2x80x94Sxe2x80x94. 
wherein Z is as defined above.
(Step 1)
Halogenated furan such as 2-bromofuran is reacted with compound (XVII) in a solvent such as N,N-dimethylformamide, toluene, xylene, benzene, tetrahydrofuran, and ethanol in the presence of palladium catalyst such as Pd(Ph3P)4 and a base such as potassium carbonate, calcium carbonate, triethylamine, and sodium methoxide to give the aimed compound (XVIII) (Suzuki reaction). The reaction temperature is room temperature to 100xc2x0 C., preferably room temperature to 80xc2x0 C. and the reaction time is 5 to 50 h, preferably 15 to 30 h.
(Step 2)
To a solution of compound (XVIII) in a solvent such as tetrahydrofuran, diethyl ether, and toluene is added a base such as n-butyllithium and sec-butyllithium, and the mixture is stirred at xe2x88x92100xc2x0 C. to 50xc2x0 C., preferably xe2x88x9280xc2x0 C. to 0xc2x0 C. for 1 min to 24 h preferably 10 min to 60 min. To the mixture is added sulfur, and the resulting mixture is reacted at xe2x88x92100xc2x0 C. to 50xc2x0 C., preferably xe2x88x9280xc2x0 C. to 0xc2x0 C. for 1 h to 24 h, preferably 1 h to 12 h to give the aimed compound (XV-5).
Method F: Synthetic method of the compound wherein Y is a thiophene ring and X is xe2x80x94Sxe2x80x94. 
wherein Z is as defined above and Hal is halogen.
The steps 1 and 2 can be carried out in a manner similar to those described in step 1 and 2 of Method E.
Method G: Synthetic method of the compound wherein Y is an oxazole ring and X is xe2x80x94Sxe2x80x94. 
wherein Z is as defined above.
To a solution of compound (XX) in a solvent such as dichloromethane, toluene, and diethyl ether is added thiophosgene in the presence of a base such as triethylamine and sodium hydroxide and the mixture is reacted at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 1 h to 48 h, preferably 1 h to 24 h to give compound (XV-7).
Method H: Synthetic method of the compound wherein Y is an oxazole ring and X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. 
wherein Z is as defined above.
(Step 1)
Compound (XXI) in a solvent such as dichloromethane and acetonitrile is reacted with a coupling reagent such as dicyclohexylcarbodiimide at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 5 min to 24 h, preferably 10 min to 2 h to give compound (XV-8).
(Step 2)
To a solution of compound (XV-8) in a solvent such as toluene and dioxane is added Lawesson""s reagent, and the mixture is reacted at 60xc2x0 C. to 150xc2x0 C., preferably 80xc2x0 C. to 120xc2x0 C. for 1 h to 24 h, preferably 2 to 12 h to give compound (XV-9).
Method I: Synthetic method of the compound wherein Y is an isooxazole ring and X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. 
wherein Z is as defined above and R14 is C1 to C3 alkyl.
(Step 1)
Compound (XXII) in a solvent such as methanol and tetrahydrofuran is reacted with hydroxylamine at 20xc2x0 C. to 100xc2x0 C., preferably 50xc2x0 C. to 80xc2x0 C. for 1 h to 24 h, preferably 2 h to 12 h to give compound (XV-10).
(Step 2)
Compound (XV-11) can be obtained in a manner similar to that described in step 2 of Method H.
The compounds which are not concretely shown in the above methods can be synthesized by a combination of the above methods A to I and well-know methods.
In the methods J to N, R5, R6, R13, Q3, and T3 (wherein R1, R2, R3, and R4 are as defined above) are as defined above. The starting material of each method is commercially available or can be synthesized by well-know methods from the compound which is commercially available.
Methods J and K are processes for construction of a pyrimidine ring, and can be carried out in accordance with well-known methods (see Journal of Chemical Society, 1937, p-364, ibid., 1943, p-388 and J. Pharm. Soc. Japan 1954, p-742).
Methods L to N are processes for introduction a guanidino group to the pyrimidine derivative obtained in the Method J and Method K, and can be carried out in accordance with well-known methods (see Journal of Chemical Society, 1948, p-581, ibid., 1946, p-1063 and Synthesis, 1988, p-460).
Method J-1: Synthesis of a pyrimidine ring wherein both RX and RY are hydrogen atom. 
wherein R5, R6 and R13 are as defined above; and RX and RY are hydrogen atom.
(Step 1)
Compound (XXIII) in a solvent such as ethanol, tetrahydrofuran, and N,N-dimethylformamide is reacted with R5xe2x80x94C(xe2x95x90S)xe2x80x94NH2 in the presence of a base such as sodium ethylate and sodium hydroxide at 0xc2x0 C. to 150xc2x0 C., preferably 60xc2x0 C. to 100xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXIV).
(Step 2)
Compound (XXIV) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with a reducing agent such as lithium aluminum hydride and lithium borohydride at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons) and the like, to give compound (XXV).
Method J-2: Synthesis of a pyrimidine ring wherein one of RX and RY is hydrogen atom. 
wherein R5, R6 and R13 are as defined above; RX is alkyl; and RY are hydrogen atom or alkyl.
(Step 1)
Compound (XXIV) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with a reducing agent such as lithium aluminum hydride and lithium borohydride at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give compound (XXVI).
(Step 2)
Compound (XXVI) in a solvent such as dichloromethane and chloroform is reacted with a oxidizing agent such as manganese dioxide, pyridinium dichromate, and pyridinium chlorochromate at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 0.5 h to 14 days, preferably 1 h to 7 days to give an aldehyde derivative. The obtained aldehyde derivative in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as RXMgBr or organometallic reagent such as RXLi at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons) and the like, to give compound (XXV).
Method J-3: Synthesis of a pyrimidine ring wherein both of RX and RY are not hydrogen atom. 
wherein R5, R6 and R13 are as defined above; RX and RY are each independently alkyl or alkyloxy; R15 is alkyl such as methyl and ethyl.
(Step 1)
Compound (XXVII) in a solvent such as ethanol, tetrahydrofuran, and N,N-dimethylformamide is reacted with R5xe2x80x94C(xe2x95x90N)xe2x80x94NH2 in the presence of a base such as sodium ethylate and sodium hydroxide, at 0xc2x0 C. to 150xc2x0 C., preferably 60xc2x0 C. to 100xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXVIII).
(Step 2)
Compound (XXVIII) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as RXMgBr or organometallic reagent such as RXLi at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h. To the mixture an acid aqueous solution such as hydrochloric acid and sulfuric acid is added , and then the resulting mixture is stirred at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give compound (XXIX).
(Step 3)
Compound (XXIX) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as RXMgBr or organometallic reagent such as RXLi at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons) and the like, to give compound (XXX).
Method J-4: Synthesis of a pyrimidine ring wherein RX and RY are same. 
wherein R5, R6 and R13 are as defined above; RX and RY are same as alkyl or alkyloxy.
(Step 1)
Compound (XXIV) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as RXMgBr or organometallic reagent such as RXLi at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons) and the like to give compound (XXV).
Method J-5: Synthesis of a pyrimidine ring wherein one of RX and RY is hydrogen atom. 
wherein R5, R6 and R13 are as defined above; one of RX and RY is hydrogen atom and the other is hydrogen atom, alkyl or alkyloxy.
(Step 1)
Compound (XXVIII) in a solvent such as ether and tetrahydrofuran or a mixed in solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as RXMgBr or organometallic reagent such as RXLi at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h. To the mixture an acid aqueous solution such as hydrochloric acid and sulfuric acid is added, and then the resulting mixture is stirred at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give compound (XXIX).
(Step 2)
Compound (XXIX) in a solvent such as ether, tetrahydrofuran, methanol, and ethanol or their mixed solvent is reacted with a reducing agent such as sodium borohydride, lithium borohydride, and lithium aluminum hydride at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons) and the like to give compound (XXV).
Method K: Synthesis of a pyrimidine ring. 
wherein R1, R5, R6 and R13 are as defined above.
(Step 1)
Compound (XXVI) in a solvent such as ethanol, tetrahydrofuran, and N,N-dimethylformamide is reacted with R5xe2x80x94C(xe2x95x90NH)xe2x80x94NH2 or its salt in the presence of a base such as sodium ethylate and sodium hydroxide at 0xc2x0 C. to 150xc2x0 C., preferably 60xc2x0 C. to 100xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXVII) or its salt.
(Step 2)
Compound (XXVII) or its salt in a solvent such as toluene and dichloroethane or without solvent is reacted with a halogenating reagent such as thionyl chloride and phosphorus oxychloride at 0xc2x0 C. to 150xc2x0 C., preferably 60xc2x0 C. to 120xc2x0 C. for 0.5 h to 12 h, preferably 1 h to 5 h to give a halogenated compound. The obtained halogenated compound in a solvent such as ethanol and tetrahydrofuran is reacted with R1NH2 at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 30xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXVIII).
(Step 3)
This step can be carried out in a manner similar to that described in step 2 of Method J-1.
Method L: Introduction of a guanidino group 
wherein R1, R2, R3, R4, R5, R6 and R13 are as defined above.
(Step 1)
Compound (XXV) in a solvent such as N,N-dimethylformamide, pyridine, and tetrahydrofuran is reacted with R3xe2x80x94NCS or R3R4NCS-Hal wherein Hal is halogen, in the presence or absence of a base such as sodium hydride at xe2x88x9220xc2x0 C. to 120xc2x0 C., preferably 0xc2x0 C. to 120xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 24 h to give compound (XXIX).
(Step 2)
To a solution of compound (XXIX) in a solvent such as methanol and tetrahydrofuran are added a heavy metal salt or heavy metal oxide such as HgO and R1R2NH, and the mixture is reacted at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XII-1).
Method M: Introduction of a guanidino group 
wherein R1, R3, R4, R5, R6 and R13 are as defined above.
(Step 1)
To a solution of compound (XXV) in a solvent such as N,N-dimethylformamide and tetrahydrofuran in the presence of a base such as sodium hydride and potassium butoxide added carbon disulfide and then alkylating reagent such as R1I and R12SO4, and the mixture is reacted at 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 60xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XII-2).
(Step 2)
Compound (XII-2) in a solvent such as methanol and N,N-dimethylformamide is reacted with R3R4NH at 0xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 100xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XII-3).
(Step 3)
Compound (XII-3) in a solvent such as methanol and N,N-dimethylformamide is reacted with R1R2NH at 20xc2x0 C. to 150xc2x0 C., preferably 40xc2x0 C. to 80xc2x0 C. for 0.5 h to 48 h, preferably 4 h to 24 h to give compound (XII-4).
Method N: Introduction of a guanidino group wherein R1 is not hydrogen atom. 
wherein R1, R2, R3, R4, R5, R6 and R13 are as defined above.
(Step 1)
This step can be carried out in a manner similar to that described in step 1 of Method L.
(Step 2)
This step can be carried out in a manner similar to that described in step 2 of Method L.
When a compound contains a functional group(s) possibly interfering the reaction such as hydroxy, mercapto, and amino group in the each step of Method A to Method N, it can previously be protected and deprotected at an appropriate stage by the method described Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley and Sons).
The term xe2x80x9cthe compounds of the present inventionxe2x80x9d herein used includes pharmaceutically acceptable salts and hydrates of the compounds. For example, salts with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid) are exemplified. These salts can be formed by usual methods. The hydrates may coordinate with an arbitrary number of water molecule.
The compounds of the present invention is not restricted to any particular isomers but includes all possible isomers and racemate.
The compounds of the present invention have an inhibitory activity against a signal derived from Ras oncogene products as shown in the experimental examples below.
Consequently, the compounds of the present invention can be used as a therapeutic agent for cancer, preferably solid tumor such as pancreatic cancer, colon cancer, and lung cancer.
When the compounds of this invention is administered to a patient for the treatment of the above diseases, they can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, liquid medicine, or the like, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation, or the like. An effective amount of the compound of this invention is formulated by being mixed with appropriate medicinal admixture such as excipient, binder, penetrant, disintegrators, lubricant, and the like, if necessary. When parenteral injection is prepared, the compound of this invention and an appropriate carrier are sterilized to formulate.
An appropriate dosage varies with the conditions of the patients, an administration route, their age, and their body weight. In the case of oral administration to an adult, the dosage can generally be between 0.01-100 mg/kg/day, preferably 0.1-20 mg/kg/day.
The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope thereof.
In the examples, the following abbreviations are used.
Me: methyl
Et: ethyl
Pr: n-propyl
i-Pr: isopropyl
Bu: n-butyl
DMF: dimethylformamide
THF: tetrahydrofuran
DMSO: dimethylsulfoxide
TBS: tert-butyldimethylsilyl
TBDPS; tert-butyldiphenylsilyl
In 1H-NMR, the value of xcex4 is represented by ppm, s is singlet, d is doublet, t is triplet, q is quartet, quit is quintet, sext is sextet, and br is broad. The value of J is represented by Hz.